tbuckley/cabot-search huggingface dataset:
IMG-11. A COMPUTERISED CLINICAL DECISION SUPPORT SYSTEM FOR DIAGNOSING CHILDREN’S BRAIN TUMOURS USING FUNCTIONAL IMAGING AND MACHINE LEARNING
Authors: Heather Rose, Arfan Ahmed, Ben Babourina-Brooks, Omar Khan, Lesley MacPherson, Karen Manias, Ashley Peake, Sana Ali, Stephanie Withey, Lara Worthington, Jan Novak, Nilou Zarinabad, Richard Grundy, Theodoros Arvanitis, Andrew Peet
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Magnetic resonance imaging is a key investigation in the diagnosis of childhood solid tumours. Advanced techniques such as diffusion weighted imaging (DWI), magnetic resonance spectroscopy (MRS) and perfusion imaging probe the underlying cellular, chemical and vascular nature of the disease. Coupled with machine learning these scanning methods show improvement in diagnostic accuracy compared with conventional imaging. Advanced image analysis is not routinely available in hospitals. We present a clinical decision support system (CDSS) developed for advanced MR analysis and interpretation. METHOD: The CDSS was developed in house. The Children’s Cancer and Leukaemia Group Functional Imaging Group (CCLGFIG) Database, a national resource, was used to provide a repository of cases together with their advanced imaging and machine learning diagnostic classifiers. A new case is displayed alongside cases in the repository with known diagnoses, including summary statistics for relevant diagnostic categories. The CDSS was made available to radiologists, in their clinical environment for technical and clinical evaluation. Structured interviews were undertaken. The CDSS was developed as a computer app for multi-centre distribution. RESULTS: 436 MRS, 240 DWI and 85 perfusion cases were available for building repositories. Machine learning classifiers showed diagnostic accuracies for the major childhood brain tumour types of 85-95%. Comparison of MRS with a data repository was found to improve non-invasive diagnosis. Results from the CDSS can be uploaded to the CCLGFIG to support multicentre research. Positive feedback on the CDSS from clinicians included: ready access to advanced analysis; simple and efficient integration into clinical workflow; and assisted interpretation of advanced analysis. DISCUSSION: Advanced MR analysis techniques provide improved non-invasive diagnostic accuracy but are difficult to implement on clinical systems due to technical, infrastructure and training limitations. CONCLUSION: We have successfully released a CDSS for paediatric cancer within the hospital environment and assessed its suitability for clinical use.
Elucidating the importance and regulation of key enhancers for human MEIS1 expression
Authors: Ping Xiang, Xining Yang, Leo Escano, Ishpreet Dhillon, Edith Schneider, Jack Clemans-Gibbon, Wei Wei, Jasper Wong, Simon Xufeng Wang, Derek Tam, Yu Deng, Eric Yung, Gregg B. Morin, Pamela A. Hoodless, Martin Hirst, Aly Karsan, Florian Kuchenbauer, R. Keith Humphries, Arefeh Rouhi
Journal: Leukemia (2022)

Abstract Myeloid ecotropic virus insertion site 1 (MEIS1) is essential for normal hematopoiesis and is a critical factor in the pathogenesis of a large subset of acute myeloid leukemia (AML). Despite the clinical relevance of MEIS1, its regulation is largely unknown. To understand the transcriptional regulatory mechanisms contributing to human MEIS1 expression, we created a knock-in green florescent protein (GFP) reporter system at the endogenous MEIS1 locus in a human AML cell line. Using this model, we have delineated and dissected a critical enhancer region of the MEIS1 locus for transcription factor (TF) binding through in silico prediction in combination with oligo pull-down, mass-spectrometry and knockout analysis leading to the identification of FLI1, an E-twenty-six (ETS) transcription factor, as an important regulator of MEIS1 transcription. We further show direct binding of FLI1 to the MEIS1 locus in human AML cell lines as well as enrichment of histone acetylation in MEIS1-high healthy and leukemic cells. We also observe a positive correlation between high FLI1 transcript levels and worse overall survival in AML patients. Our study expands the role of ETS factors in AML and our model constitutes a feasible tool for a more detailed understanding of transcriptional regulatory elements and their interactome.
Estimation of the Prevalence of Delayed Dispensing Among Opioid Prescriptions From US Surgeons and Dentists
Authors: Kao-Ping Chua, Jennifer F. Waljee, Michael A. Smith, Shreya Bahl, Romesh P. Nalliah, Chad M. Brummett
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Dispensing of opioid prescriptions from dentists and surgeons more than 30 days after writing, or delayed dispensing, could be a potential indicator that opioids were used for reasons or during a time frame other than that intended by the prescriber. The prevalence of delayed dispensing is unknown. Whether laws can prevent delayed dispensing by shortening the maximum period between prescription writing and dispensing is also unknown. <h3>Objective</h3> To estimate the prevalence of delayed dispensing among opioid prescriptions from surgeons and dentists, assess the maximum period US states allow between controlled substance prescription writing and dispensing, and evaluate whether laws shortening this period decrease delayed dispensing of opioid prescriptions from surgeons and dentists. <h3>Design, Setting, and Participants</h3> In this cross-sectional analysis, data from the IQVIA Formulary Impact Analyzer (representing 63% of US prescriptions) were used to identify opioid prescriptions from surgeons and dentists dispensed from 2014 through 2019. <h3>Main Outcomes and Measures</h3> Among opioid prescriptions dispensed in 2019, the proportion with delayed dispensing was calculated. Using legal databases, the maximum state-allowed period between controlled substance prescription writing and dispensing as of December 2019 was examined. Using a difference-in-differences design and 2014 to 2019 data, changes in delayed dispensing prevalence were evaluated among opioid prescriptions from surgeons and dentists after a Minnesota law was enacted in July 2019 precluding opioid prescription dispensing more than 30 days after writing. Control states allowed dispensing beyond this period. <h3>Results</h3> In 2019, the database included 20 858 413 opioid prescriptions from surgeons and dentists for 14 789 984 patients; 8 582 029 (58.0%) were female. The mean (SD) patient age was 47.1 (19.3) years. Of prescriptions included, 194 452 (0.9%) had delayed dispensing. As of December 2019, the maximum period between drug writing and dispensing was 180 days in 18 and 43 states for Schedule II and III drugs, respectively. Compared with control states, Minnesota's law decreased delayed dispensing prevalence by 0.22 percentage points (95% CI, −0.32 to −0.13 percentage points). <h3>Conclusions and Relevance</h3> In this cross-sectional study, 194 452 opioid prescriptions from surgeons and dentists were dispensed more than 30 days after writing. To mitigate any prescription opioid misuse associated with delayed dispensing, policy makers could shorten the maximum period between writing and dispensing of opioid prescriptions from surgeons and dentists.
ARV-471, an estrogen receptor (ER) PROTACdegrader, combined with palbociclib in advanced ER+/human epidermal growth factor receptor 2–negative (HER2-) breast cancer: Phase 1b cohort (part C) of a phase 1/2 study.
Authors: Erika P. Hamilton, Anne F. Schott, Rita Nanda, Haolan Lu, Chi Fung Keung, Richard Gedrich, Janaki Parameswaran, Hyo S. Han, Sara A. Hurvitz
Journal: Journal of Clinical Oncology (2022)

TPS1120 Background: ARV-471 is a novel, potent, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader that selectively targets the ER. In xenograft models, ARV-471 demonstrated substantially greater ER degradation and antitumor activity compared with the selective ER degrader fulvestrant. In the phase 1 dose escalation portion (Part A) of the first-in-human phase 1/2 study, ARV-471 monotherapy was well tolerated and showed antitumor activity in patients with ER+/HER2- locally advanced or metastatic breast cancer who had previously received endocrine therapy and a cyclin-dependent kinase (CDK)4/6 inhibitor; the clinical benefit rate (rate of confirmed complete or partial response or stable disease ≥24 weeks) was 40% (95% CI: 26%–56%) in 47 evaluable patients. The phase 2 VERITAC expansion cohort (Part B) is further evaluating ARV-471 monotherapy in this patient population. Palbociclib, a CDK4/6 inhibitor, plus fulvestrant is a standard treatment option for patients with ER+/HER2- breast cancer who have had disease progression on endocrine therapy. ARV-471 plus palbociclib resulted in substantially greater tumor growth inhibition in xenograft models compared with palbociclib plus fulvestrant, supporting further investigation of the ARV-471 plus palbociclib combination in patients with ER+ breast cancer. Here we describe Part C of the phase 1/2 study, which evaluates the safety and clinical activity of ARV-471 plus palbociclib in patients with breast cancer who previously received endocrine therapy. Methods: Eligible patients (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- advanced breast cancer and have received ≥1 prior endocrine therapy and ≤2 prior chemotherapy regimens for advanced disease; prior CDK4/6 inhibitor therapy is permitted. Patients with known symptomatic brain metastases requiring steroids are excluded. ARV-471 and palbociclib will be administered orally once daily in 28-day cycles; ARV-471 will be given continuously and palbociclib for 21 days followed by 7 days off treatment. Primary objectives are to evaluate the safety and tolerability of ARV-471 plus palbociclib and select the recommended phase 2 dose and schedule of the combination (based on the incidence of dose-limiting toxicities during the first cycle and the frequency and severity of adverse events and laboratory abnormalities). Secondary objectives are to assess preliminary antitumor activity of ARV-471 plus palbociclib (based on overall response rate per Response Evaluation Criteria in Solid Tumors v1.1, clinical benefit rate, progression-free survival, and duration of response) and pharmacokinetic parameters. Clinical trial information: NCT04072952.
IMMU-21. Targeting the adenosinergic immune suppression pathway in high grade glioma synergizes with innate immune checkpoint blockade
Authors: Yifan Liu, Senthil Lakshmana Chetty, Allison Cole, Joselyn Cruz Cruz, Eric Hoffmeyer, Rajeev Vibhakar, Sujatha Venkataraman, Siddhartha Mitra
Journal: Neuro-Oncology (2022)

Abstract Immune response in the tumor microenvironment is modulated by the conversion of eATP to AMP to adenosine via the ecto-enzymes CD39 and CD73. Overexpression of CD73 in tumors leads to an increase in extracellular adenosine concentration and decrease in eATP, resulting in immune suppression. In this study, CD73 knockouts were created in adult and pediatric glioma cell lines (DIPG17, T3691, BT245) and used to quantify the effects of CD73 knockout on macrophage phagocytosis in the presence of extracellular AMP. In cell line DIPG17, CD73 knockout significantly increased phagocytosis with and without external AMP compared to the WT. In the WT condition, addition of AMP significantly reduced phagocytosis, while this decrease was not significant in the CD73-KO. The addition of anti-CD47 antibody significantly increased phagocytosis with external AMP in the WT condition. Similar results were obtained with cell line T3691. However, CD73 knockout combined with anti-CD47 treatment and external AMP showed significantly greater phagocytosis than the WT condition. This suggests that a combination of anti-CD73 and anti-CD47 treatment may be more effective in the tumor microenvironment. Lastly, in cell line BT245, CD73 knockout significantly increased phagocytosis as seen in the other cell lines. However, no significant difference was observed between WT and CD73-KO with extracellular AMP or anti-CD47. In vivo studies were conducted in orthotopic xenograft mouse models with DIPG17 CD73 knockout cells. Combination treatment with anti-CD47 antibody significantly decreased tumor burden and prolonged survival in the CD73-KO tumors compared to anti-CD47 treated DIPG13-WT tumors. We conclude that the CD73 adenosinergic pathway and the CD47-SIRPα pathway may present a target for immunotherapy in pediatric and adult gliomas.
Pyrotinib combined with EC-TH neoadjuvant therapy for patients with HER2-positive breast cancer: A multicenter, randomized, phase II, open-label trial.
Authors: Xiangmei Zhang, Shuo Zhang, Zhong Li, Fengling Niu, Haifeng Cai, Xianqiao Li, Meng Han, Ruixue Huang, Yunjiang Liu
Journal: Journal of Clinical Oncology (2022)

e12604 Background: Neoadjuvant therapy plays an important role in improving the clinical efficacy for patients with stage II-III epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI), combined with capecitabine have demonstrated a promising anti-tumour activity in metastatic breast cancer. Here, we conducted a multicenter, randomized, phase II, open-label trial aiming exploring the outcomes of adding pyrotinib to EC-TH neoadjuvant therapy. Methods: Patients aged 18–65 years old with invasive carcinoma, cT1-4N0-3M0 stage, HER2-positive breast cancer were enrolled. Cases were randomly assigned into neoadjuvant therapy with four cycles of epirubicin and cyclophosphamide followed by four cycles of docetaxel (or Paclitaxel for Injection, albumin bound) and trastuzumab (EC-TH), or pyrotinib (400mg day 1-21) combined with EC-TH. Results: 56 patients had completed 8 cycles of neoadjuvant therapy (40 in the treatment group and 16 in the controlled group). 20 patients underwent radical surgery after neoadjuvant therapy. Compared with EC-TH along (37.5%, 3/8), the addition of pyrotinib to EC-TH neoadjuvant chemotherapy (py+EC-TH) significantly increased the pathological complete response (pCR)rate (75%, 9/12) in patients with HER2-positive breast cancer. The objective response rate (ORR) was 87.5% (7/8) vs 100% (12/12) . The most common adverse effects (AEs) in the treatment group was diarrhoea with grade 3 occurred in 3 cases (7.5% 3/40), which most limited in the first treatment cycle. No grade 3 diarrhoea was observed in controlled group. Other AEs including leukopenia occurred similarly in both groups and no cardiovascular dysfunction was observed. Conclusions: Pyrotinib added to EC-TH neoadjuvant therapy significantly increased the pCR rate, suggesting an applicable strategy for HER2-positive breast cancer. Clinical trial information: NCT04290793.
Systematic assessment of online health information related to drug therapy for non-small cell lung cancer.
Authors: Yu-Hui Xu, Yi-Fan Zheng, Hui-Min Yang, Xiao Chen, Ke-Jing Tang
Journal: Journal of Clinical Oncology (2022)

e18626 Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Patients increasingly use the internet for drug therapy information that may influence decision-making, drug adherence, and self-management. However, online drug therapy information is prone to quality and readability issues. We systemically assess online drug therapy information for patients with NSCLC in terms of quality, suitability, reliability and readability. Methods: NSCLC online drug therapy websites were searched with three terms using three major engines (Google, Yahoo and Bing). Validated tools were used to assess the content in terms of quality (DISCERN), suitability (Suitability Assessment of Materials [SAM]), reliability (Journal of the American Medical Association [JAMA] benchmarks and the Health on the Net [HON] code), readability (Flesch-Kincaid Grade Level). The scores were compared in drug therapy and affiliation subgroups. Results: A total of 52 websites were included. The median quality score was 48.8 (interquartile range [IQR], 39.5-57.0), or fair (39-50). The quality scores were not statistically significant between different subgroups. The median suitability score was 43.8% (40.6%-46.4%), or adequate (40%-69%). The commercial websites showed the highest median suitability score of 45.2%, which was significantly higher than that of non-profit websites ( P &lt; 0.05). The average readability was at a grade of 10.6 level using the Flesch-Kincaid scale which was significantly higher than the traditionally recommended grade-six level ( P＜0.001). The median reliability scores of commercial websites were observably higher than non-profit websites ( P＜0.05). Around 40% of websites were HON code accredited. Conclusions: Most online resources for NSCLC have fair quality, adequate suitability, and poor readability. Reliability was of a moderate level. Therefore, healthcare providers should be cautious when referring patients to online health information and the online information for NSCLC has great room for improvement.[Table: see text]
Body composition changes in a 12-week exercise intervention for breast cancer patients.
Authors: Chloe Asato, Alanna Vance, Shirley Cheng, Shannon Lim, Paulette Yamada, Cheri Teranishi-Hashimoto, John Shepherd, Jami Aya Fukui
Journal: Journal of Clinical Oncology (2022)

e12500 Background: Evidence has linked weight gain and obesity to increased breast cancer risk, poorer outcomes, decreased survivorship, and increased risk of recurrence. Adjuvant therapies can increase weight gain, making tailored exercise interventions beneficial in maintaining a healthy weight. In this study, body composition changes were examined after a 12-week exercise program in a cohort of breast cancer survivors. Methods: The Breast Cancer Exercise Rehabilitation Research Study recruited breast cancer survivors to undergo a 12-week exercise program (NCT04013568) and examine body composition changes. Measurements taken included anthropometry (waist circumference, waist-to-hip ratio, BMI), DXA body composition measurements (fat mass-visceral and subcutaneous, trunk to limb, muscle mass-appendicular, and whole body), and BIA (Bio-electrical Impedance Analysis-muscle, fat, and water). 34 participants completed the exercise program and baseline and post-12-week measurements were obtained. Descriptive statistics and a paired t-test analysis was done to analyze changes in body composition using SAS onDemand. A correlation analysis between measurements simple to do in clinic and DXA measurements were run to determine proxy use for DXA. Results: After a 12-week exercise program, reductions in body fat via DXA scan, BIA, and InBody (whole body fat, whole body fat %, trunk fat, leg fat, body fat %, hip width at maximum girth, body fat mass, and percent body fat) were observed. Additionally, increases in lean mass (Appendicular Lean Mass (ALM)/height 2 , Appendicular Lean/height 2 , ALM index, and lean body mass), whole body mass measured by DXA, basal metabolic rate, water retention (extracellular water and total body water), and skeletal muscle mass were observed. Correlation analysis revealed BMI can be used as a surrogate measure for whole body mass measured by DXA (r=0.91, p&lt;0.001) and can be utilized to measure change over time. Skinfold sum showed moderate correlation for measuring subcutaneous fat mass by DXA (r=0.45, p=0.0096). Conclusions: In our population of breast cancer survivors, a 12-week exercise program did show various changes in body composition according to InBody, DXA, and BIA measurements. DXA and InBody measurements were feasible, making it readily available for patients. Additionally, simple measures such as BMI and skinfold sum showed moderate to strong correlation with DXA measurements, validating use of these measurements in routine practice. Clinical trial information: NCT04013568. [Table: see text]
Codon-specific KRAS mutations predict overall survival benefit of trifluridine/tipiracil in metastatic colorectal cancer.
Authors: Joris van de Haar, Xuhui Ma, Salo N. Ooft, Pim W. van der Helm, Louisa Rose Hoes, Sara Mainardi, Lodewyk F.A. Wessels, Emile E. Voest
Journal: Journal of Clinical Oncology (2022)

3593 Background: Genomics-based precision medicine has greatly improved how patients with cancer are being treated with targeted agents, but clinical-grade genomic biomarkers for chemotherapies are currently lacking. The chemotherapeutic trifluridine/tipiracil (FTD/TPI) is approved for the treatment of late-stage metastatic colorectal cancer (mCRC). We aimed to find genomic biomarkers to improve patient selection for FTD/TPI treatment in mCRC. Methods: In a discovery cohort of FTD/TPI-treated mCRC patients (n = 37), genome-wide somatic variants were tested for association with treatment duration and overall survival (OS). In vitro drug testing on isogenic cell lines and patient-derived mCRC organoids, as well as a re-analysis of the double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800) were performed to support our findings. Results: In the discovery cohort, KRAS codon G12 (KRAS G12 ) mutation status was the only significant genomic determinant of poor outcome of FTD/TPI treatment, which could be replicated in vitro by drug testing on isogenic cell lines and PDOs. In these models, KRAS G12 mutations were associated with increased resistance to FTD-induced (geno)toxicity in vitro. KRAS G12 -based resistance was absent for the closely related chemotherapeutic 5-FU. In the RECOURSE study, KRAS G12 mutations were predictive biomarkers for reduced OS benefit of FTD/TPI vs placebo (unadjusted interaction P= 0.0017, adjusted interaction P= 0.017). For patients with KRAS G12 mutations, OS was not significantly prolonged with FTD/TPI vs placebo (n = 279; HR, 0.97; 95% CI, 0.73−1.20; P= 0.85). An exploratory analysis showed that the KRAS G13 mutant subgroup demonstrated clearly prolonged OS with FTD/TPI vs placebo (n = 60; unadjusted HR, 0.29; 95% CI, 0.15−0.55; P&lt; 0.001; adjusted HR, 0.20; 95% CI, 0.092−0.45; P&lt; 0.001), which was significantly more pronounced as compared to the KRAS G12 mutant and KRAS WT populations (adjusted interaction P&lt; 0.001 and P= 0.036, respectively). Conclusions: Together, KRAS G12 mutations were associated with reduced OS benefit of FTD/TPI treatment, with potential implications for ̃28% of patients with metastatic colorectal cancer now considered for treatment with FTD/TPI. Furthermore, our data show that genomics-based precision medicine may be possible for a subset of chemotherapies.